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(Circulation Research. 2003;93:515.)
© 2003 American Heart Association, Inc.

Molecular Medicine

Fas and Fas-Associated Death Domain Protein Regulate Monocyte Chemoattractant Protein-1 Expression by Human Smooth Muscle Cells Through Caspase- and Calpain-Dependent Release of Interleukin-1

Friedemann J. Schaub, W. Conrad Liles, Nicola Ferri, Kirsten Sayson, Ronald A. Seifert, Daniel F. Bowen-Pope

From the Departments of Pathology (F.J.S., W.C.L., N.F., K.S., R.A.S., D.F.B.-P.) and Medicine (W.C.L.), University of Washington, Seattle, Wash.

Correspondence to Daniel F. Bowen-Pope, University of Washington, Department of Pathology, Box 357470, Seattle, WA 98195-7470. E-mail: bp{at}u.washington.edu

We previously reported that treatment of human vascular smooth muscle cells (SMCs) with proapoptotic stimuli, including Fas ligand plus cycloheximide (FasL/Chx), or overexpression of Fas-associated death domain protein (FADD) result in increased expression of monocyte chemoattractant protein-1 (MCP-1) and other proinflammatory genes. In this study, we demonstrate that Fas/FADD-induced MCP-1 upregulation is driven by an autocrine/paracrine signaling loop in which interleukin (IL)-1 synthesis and release are activated through caspase- and calpain-dependent processes. Untreated SMCs contain very little IL-1 protein or transcript. Both were increased greatly in response to Fas/FADD activation, primarily through an autocrine/paracrine pathway in which secreted IL-1 stimulated additional IL-1 synthesis and release. Caspase 8 (Csp8) activity increased in response to FasL/Chx treatment, and Csp8 inhibitors markedly reduced IL-1 release and MCP-1 upregulation. In contrast, Csp8 activity was not significantly increased in response to FADD overexpression and caspase inhibitors did not effect FADD-induced MCP-1 upregulation. Both FasL/Chx treatment and FADD overexpression increased the activity of calpains. Calpain inhibitors reduced IL-1 release and MCP-1 upregulation in both FADD-overexpressing SMCs and FasL/Chx-treated SMCs without blocking Csp8 activity. This indicates that calpains are not required for activation of caspases and that caspase activation is not sufficient for IL-1 release and MCP-1 upregulation. These data suggest that calpains play a dominant role in Fas/FADD-induced IL-1 release and MCP-1 upregulation and that caspase activation may function to amplify the effects of calpain activation.

Key Words: apoptosis • interleukin • inflammation • calpain • monocyte chemoattractant protein-1

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